Propofol (2,6-diisopropylphenol or 2,6-bis(1-methylethyl)-phenol)) is a widely used injectable, alkylphenol sedative-hypnotic agent widely used for induction and maintenance of general anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibrium is approximately 1 to 3 minutes, which accounts for the rapid induction of anesthesia. Thus, propofol has the advantage of a rapid onset after infusion or bolus injection, along with a short recovery period of several minutes, instead of hours. Since its introduction in the late 1980s, propofol's versatility and favorable pharmacokinetics have made it a popular choice for induction and maintenance of anesthesia.
Propofol has the disadvantage of causing pain upon injection. Among 33 clinical problems identified in the field of anesthesia, propofol-induced pain has been ranked seventh, when both clinical importance and frequency were considered (Macario A. et al., Anesth. Analg. 88:1085-1091, 1999). The mechanism by which propofol induces pain on injection is still not known. Various factors have been hypothesized to be responsible for this adverse effect, such as the osmality of the solvent used in the preparation, the pH of the preparation, or the concentration of propofol in the aqueous phase of the emulsion (Doenicke A. W. et al., Anesth. Analg. 82:472-474, 1996). One mechanism for the pain experienced after injection of propofol is thought to be the direct stimulation of venous nociceptive receptors or free nerve endings, the nerve impulse being transmitted by thinly myelinated A delta fibers (Arndt J. O. and Klement W., Br. J. Anaesth., 66:189-195, 1991).
Many methods have been investigated to reduce the incidence and severity of propofol-induced pain, many of which involve the temperature of the formulation, size and site of venous cannulation, speed of injection, and analgesic interventions (Picard P. and Tramer M. R., Anesth. Analg. 90:963-969, 2000). Numerous pharmacological treatments, various doses and combinations, alternative methods of administration, and physical interventions have been tested, often with a clear physiological basis. Propofol has been warmed or cooled, injected faster or more slowly, with or without tourniquet, diluted or undiluted. Local anesthetics, opioids, nonsteroidal anti-inflammatory drugs, ketamine, metoclopramide, droperidol, and other chemical substances have been evaluated.
Pain on injection induced by propofol has been found to be reduced by a preceding injection of lignocaine (also referred to as lidocaine) (McCulloh M. J. and Lees N. W., Anaesthia, 40:1117-1120, 1985). Low concentrations of lidocaine mixed with propofol (e.g., 1:10) and thereby diluted to a 0.1% solution almost instantaneously prevent propofol-induced pain on injection. Lidocaine's effects on vascular smooth muscle have been implicated (Nicol M. E. et al., Anaesthesia, 46:67-69, 1991). An effect of lidocaine on propofol-induced pain separate from its local anaesthetic action has also been proposed. Alternative explanations for the efficacy of lidocaine on injection pain caused by propofol include: lidocaine hydrochloride is a weak free base-cation solution which, when exposed to lipids, liberates protons as the free base dissolves in the lipids, thereby decreasing the pH of the mixture; the lower pH produced after mixing lidocaine with propofol reduces the concentration of propofol anions since propofol is a weak acid with a pKa of 11. This would result in an increased amount of propofol that migrates into the lipid phase, resulting in reduced pain on injection (Klement W. and Arndt J. O., Br. J. Anacsth., 67:281-284, 1991; Babl J. et al., Euro. J. Hospital Pharmacy, 1:15-22, 1995).
It has also been proposed that local anesthetics may bind to the vascular endothelium and that binding of the local anesthetic directly to propofol may also reduce its anesthetic effects. This would explain the observed reduction of propofol-induced pain on injection by metoclopramide, a structural analog of procainamide that is almost entirely lacking in local anaesthetic activity (Ganta R. and Fee. J. P. H., Br. J. Anaesthesia, 69:316-317, 1992). Like lignocaine, the pH-lowering effect of the metcolpramide solution has been suggested as the principal mechanism for its reported pain relieving effect, as well (Eriksson, M. et al., Br. J. Anaesthesia, 78:502-506, 1997).
Propofol is very lipid soluble and only slightly soluble in water and, thus, is formulated in an oil-in-water emulsion. The commercially available form of propofol, DIPRIVAN (for human use) and RAPINOVET (for veterinary use), is an opaque oil-in-water emulsion containing lipids and egg lecithin as an emulsifying agent (ASTRAZENECA, Wilmington, Del.). The DIPRIVAN 1% emulsion-type formulation contains 10 mg/mL propofol, 100 mg/mL soybean oil, 22.5 mg/mL glycerol, 12 mg/mL egg lecithin, and 0.005% w/v disodium edentate (EDTA), and is reported by the manufacturer to have a pH of 7.0 to 8.5 at time of packaging (DIPRIVAN, Injectable Emulsion Propofol, Professional Information Brochure, ASTRAZENECA, April 2001). Although the manufacturer's professional information brochure indicates that the propofol formulation also contains sodium hydroxide, there is no indication that any agent is added to the formulation to specifically maintain the alkalotic pH. The present inventor has determined that the pH of commercially available propofol formulations is significantly lower at the time the formulation is to be administered than that represented in the literature. This difference in pH may be explained by at least one of two phenomenon: (1) inaccurate measurement at time of manufacture/packaging (e.g., due to calibration drift or variations in moisture or temperature); and (2) the propofol formulation “drifts” such that, at the time of administration, the pH is significantly reduced, typically 5.8 to 6.0, or less. In contrast, according to the information brochure (July 2002) provided with a generic form of propofol that is commercially available from BAXTER Healthcare Corporation (Deerfield, Ill.; U.S. Pat. No. 6,147,122), the 1% propofol injectable emulsion has a pH of 4.5 to 6.6 at time of packaging. Injection pain is experienced with both DIPRIVAN and generic propofol.
The present inventor has determined that the pain associated with propofol administration can be significantly reduced or eliminated by adjusting the pH of the propofol formulation such that the pH is at least 6.5 at time of administration.